Crystal structure of LGR ligand α2/β5 from Caenorhabditis elegans with implications for the evolution of glycoprotein hormones.
Crystal structure of LGR ligand α2/β5 from Caenorhabditis elegans with implications for the evolution of glycoprotein hormones.
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DOI：
10.1073/pnas.2218630120
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发表时间：
2023-01-03
影响因子：
11.1
通讯作者：
Hendrickson, Wayne A.
中科院分区：
文献类型：
--
作者：
Gong, Zhen;Wang, Wei;El Omari, Kamel;Lebedev, Andrey A.;Clarke, Oliver B.;Hendrickson, Wayne A.
关键词：
脊椎动物的糖蛋白激素通过LGR受体起作用，介导生殖器官和甲状腺的生理反应。这些激素是由亲缘关系较远的α和β蛋白链组成的二硫桥异二聚体。虽然糖蛋白激素仅存在于脊椎动物中，但所有两侧对称的动物都具有同源二聚体α2β5及其同源LGR受体。本文描述的线虫α2β5激素的结构为重建LGR配体家族的分子进化提供了基础——从基础后生动物（例如海绵和栉水母）中假定的α2同型二聚体到人类的糖蛋白激素。一类富含亮氨酸重复序列的g蛋白偶联受体（lgr）与其同源配体配合时可介导多种生理反应。lgr存在于所有后生动物中。在人类中，LGR配体包括糖蛋白激素（GPHs）、绒毛膜促性腺激素（hCG）、黄体生成素、促卵泡激素（hFSH）和促甲状腺激素（hTSH）。这些激素是半胱氨酸结蛋白链的αβ异源二聚体。lgr及其配体链共同进化。在双侧动物和脊索动物中都存在的祖先激素同源物被鉴定为α2β5。我们利用单波长异常衍射和分子替换法测定了秀丽隐杆线虫(Ceα2β5) α2β5激素的结构。e - α2β5和其他α2β5激素一样是未糖基化的。Hsα2β5（人α2β5的同源物）和hTSH都激活同一受体（hTSHR）。尽管与脊椎动物GPHs的序列相似性很小，但除了核心二硫桥的半胱氨酸模式外，Ceα2β5在结构上基本相似；与hCG和hFSH相比，其α2和β5亚基更为对称。这种准对称表明α2β5和αβ异源二聚体存在假设的同二聚体前体。已知结构和其他LGR配体序列的AlphaFold模型提供了从早期后生动物到当今gph的LGR配体分子进化的代表。Ceα2β5的实验结构验证了其AlphaFold模型，Hsα2β5也验证了该模型；模型中Hsα2β5:hTSHR复合物的界面特征与实验中hTSH:hTSHR结构相似。
Glycoprotein hormones of vertebrate animals act through LGR receptors, which mediate physiological responses in reproductive organs and the thyroid. These hormones are disulfide-bridged heterodimers composed from remotely related α and β protein chains. While glycoprotein hormones are found only in vertebrates, all bilaterally symmetric animals possess homologous dimers, identified as α2β5, and their cognate LGR receptors. The structure described here for the α2β5 hormone from a nematode worm provides a basis for reconstructing the molecular evolution of the family of LGR ligands—from a putative α2 homodimer in basal metazoan animals (sponges and comb jellies, for example) to glycoprotein hormones in humans. A family of leucine-rich-repeat-containing G-protein-coupled receptors (LGRs) mediate diverse physiological responses when complexed with their cognate ligands. LGRs are present in all metazoan animals. In humans, the LGR ligands include glycoprotein hormones (GPHs) chorionic gonadotropin (hCG), luteinizing hormone, follicle-stimulating hormone (hFSH), and thyroid-stimulating hormone (hTSH). These hormones are αβ heterodimers of cystine-knot protein chains. LGRs and their ligand chains have coevolved. Ancestral hormone homologs, present in both bilaterian animals and chordates, are identified as α2β5. We have used single-wavelength anomalous diffraction and molecular replacement to determine structures of the α2β5 hormone from Caenorhabditis elegans (Ceα2β5). Ceα2β5 is unglycosylated, as are many other α2β5 hormones. Both Hsα2β5, the human homolog of Ceα2β5, and hTSH activate the same receptor (hTSHR). Despite having little sequence similarity to vertebrate GPHs, apart from the cysteine patterns from core disulfide bridges, Ceα2β5 is generally similar in structure to these counterparts; however, its α2 and β5 subunits are more symmetric as compared with α and β of hCG and hFSH. This quasisymmetry suggests a hypothetical homodimeric antecedent of the α2β5 and αβ heterodimers. Known structures together with AlphaFold models from the sequences for other LGR ligands provide representatives for the molecular evolution of LGR ligands from early metazoans through the present-day GPHs. The experimental Ceα2β5 structure validates its AlphaFold model, and thus also that for Hsα2β5; and interfacial characteristics in a model for the Hsα2β5:hTSHR complex are similar to those found in an experimental hTSH:hTSHR structure.
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影响因子：
2.9
作者：
Fan, XL;She, YM;Mahuran, DJ
通讯作者：
Mahuran, DJ
影响因子：
5.2
作者：
Cahoreau C;Klett D;Combarnous Y
通讯作者：
Combarnous Y
影响因子：
4.3
作者：
Fan, XL;She, YM;Mahuran, DJ
通讯作者：
Mahuran, DJ
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.1206643109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Jiang, Xuliang;Liu, Heli;He, Xiaolin
通讯作者：
He, Xiaolin